Pezhman, Laleh (2022). Modulation of PEPITEM pathway in type 2 diabetes. University of Birmingham. Ph.D.
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Pezhman2022PhD.pdf
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Abstract
Adiponectin is an anti-inflammatory and insulin-sensitising hormone produced by adipose tissue that regulates lymphocyte migration across the endothelium through the PEPITEM pathway. Impaired bioactivity of the PEPITEM pathway, due to decreased expression of adiponectin receptor 1 (AdipoR1) and AdipoR2 on B cells, has been reported in elderly and T1DM. However, the modulation of this pathway is unknown in T2DM and obesity.
Here, we first characterised the role of CDH13 (Cadherin-13), in regulating anti-inflammatory effects of adiponectin focusing on PEPITEM pathway. We showed that adiponectin strongly inhibited lymphocyte migration either by action on the lymphocytes (previously published) or directly on endothelium. We found that CDH13 and AdipoR1/R2 were expressed by endothelial cells and individual knock down of these receptors was sufficient to dampen the endothelial response and abrogated the inhibitory effects of adiponectin on lymphocyte transmigration.
To investigate the effects of hyperglycemia on leukocyte-endothelium interaction in vitro, either blood endothelial cells (BEC) or lymphocytes were exposed to high concentration of glucose (HG). HG treatment of BEC reduced the ability of endothelial cells to support lymphocyte transmigration, which was restored by insulin and metformin supplementation. In contrast, HG treatment of lymphocytes increased their adhesion and transmigration across the endothelium, suggesting activation of lymphocytes by HG treatment. Since, the expression of AdipoR1/R2 on B cells remained unchanged following HG treatment, modulation of these receptors is not a suggested mechanism for HG effects.
Given that circulating levels of adiponectin are significantly decreased in patients with obesity and T2DM, there is a distinct possibility that these individuals are unable to generate sufficient PEPITEM and therefore would benefit from replacement therapy. Using obesogenic-dietary preclinical models, we investigated the efficacy of PEPITEM to limit pancreatic islet damage and its ability to modulate systemic leukocyte trafficking. PEPITEM reduced the expansion of pancreatic islets size and limited T cells recruitment in visceral adipose tissue both prophylactically and therapeutically. In particular, therapeutic administration of PEPITEM increased the number of lymphocytes in secondary lymphatic organs, suggesting PEPITEM has the capacity to control lymphocyte egress from secondary lymphoid organs.
Our observations highlight a crucial role of CDH13 in functionality of PEPITEM pathway and indicate that HG differentially affects the endothelium and lymphocyte behaviour to support the lymphocyte recruitment. Our in vivo results, underline the importance of PEPITEM in the control of lymphocyte transmigration during obesity-induced inflammation and offers a potential therapeutic role for PEPITEM to overcome obesity related changes which occur in early stages of disease.
| Type of Work: | Thesis (Doctorates > Ph.D.) | ||||||||||||||||||
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| Award Type: | Doctorates > Ph.D. | ||||||||||||||||||
| Supervisor(s): |
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| Licence: | All rights reserved | ||||||||||||||||||
| College/Faculty: | Colleges (2008 onwards) > College of Medical & Dental Sciences | ||||||||||||||||||
| School or Department: | Institute of Inflammation and Ageing | ||||||||||||||||||
| Funders: | None/not applicable | ||||||||||||||||||
| Subjects: | R Medicine > R Medicine (General) R Medicine > RM Therapeutics. Pharmacology |
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| URI: | http://etheses.bham.ac.uk/id/eprint/13138 |
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